Development of the autoimmune B cell repertoire in MRL-lpr/lpr mice.
The processes responsible for the production of autoantibodies have been shown to include both Ag-specific and generalized (polyclonal) forms of B cell activation. The relative contribution and temporal association of these processes to the genesis of systemic autoimmunity are incompletely understood. To study this relationship, the B cell repertoires of MRL-lpr/lpr mice were analyzed by ELISA spot assay over an 8-mo period. Between 6 and 12 wk of age, the number of splenic lymphocytes producing antibodies reactive with both autoantigens and conventional Ag increased proportionately. The repertoires of MRL-lpr/lpr mice under 12 wk were dominated by IgM-secreting B cells that showed no bias toward the production of specific autoantibodies. From 12 to 38 wk of age, an increasing proportion of animals developed repertoires dominated by IgG-secreting B cells that were skewed toward reactivity against one or very few (auto)antigens. Although there was no single Ag against which all mice developed skewed reactivity, 55% of MRL-lpr/lpr adults had increased numbers of B cells producing antibodies to the Sm Ag and 13 to 16% developed increased reactivity toward DNA, myosin, histone, thyroglobulin, or T cells. These data indicate that generalized (polyclonal) B cell activation dominates early repertoire development whereas (auto)-antigen-specific responses become increasingly important during the latter stages of disease in these autoimmune-prone mice.
Klinman
D M
DM
Infectious Diseases Branch, National Institute of Neurological and Communicative Disorders and Stroke, Bethesda, MD 20892.
Eisenberg
R A
RA
Steinberg
A D
AD
D000367:Age Factors; D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D004247:DNA / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007958:Leukocyte Count; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D009218:Myosins / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins
D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D007075:Immunoglobulin M; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins; D010047:Ovalbumin; D004247:DNA; D006433:Hemocyanins; D009218:Myosins